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summaries of first two talks, London SM seminar

There's a second Rusbridge one on pain and after surgery management that I will also post as I think it would be of interest to many; still finishing that summary. There were 10 papers so it is taking me a while to do summaries for them all.

Both SM and MVD are known problems within the Dutch CKCS population that have reduced life expectancy from 13-15 years (for dogs of similar weight) to 8-10 years

Because SM has only been addressed on a consulting basis (eg when people have brought in an affected dog) it is impossible to make estimates of prevalence. However SM is expected to become more prevalent because asymptomatic cavaliers have been allowed to breed

Due to a private initiative from a Dutch breeder that started in 2002, 196 CKCS have been MRI-screened for SM. The point of screening is to identify the best possible breeding animals. Of these:
30% were graded A/B; 14% were C; 39% D, 13% E and 4% F, using the Rusbridge grading scheme. Overall 56% had SM. Blood samples were taken for all dogs for DNA research.

In a two year period, 2004-2006, Dutch breeders have increased the number of dogs scanning as A/B from 10% to about 25% by concentrating on screening relatives of clear dogs rather than random dogs

Early observations: 14 Breeders demonstrating best use of their clear dogs
Coping with large number of affected dogs
Initially A x D crosses predominated (not enough As)
Now A x A mating is an option
Up to 4 generations “SM clear”
SM Clear dogs related to other SM clear dogs
No SM affected dogs from A x A crosses

Summary of talk:

(Clare Rusbridge read this paper as Paul Mandigers could not attend)

Of a population of 74 screened for one project, 75 per cent had SM. There is a wide range of affectedness -- not all cases are painful (about 30%). The worst pain is experienced when the syrinxes are wide, and early onset cases tend to be the worst as well.

It is unrealistic to expect to eliminate SM as there are too many affected dogs (similar to the case with MVD) and some dogs with SM are free of clinical signs making it hard to pinpoint dogs with it by breeding age unless MRId. So the goal must be to increase the number of symtom-free CKCS.

Breeders are in a difficult place because they are told, don’t breed from affected dogs. However: individual breeders may not have any clear dogs; and affected dogs may be valuable champions and valuable in other respects eg good hearts. Breeeders also really need a screening test for young dogs, but because the condition is progressive, we don;t currently have the ability to pick an ideal age for screening. The best compromise (and that used by the Dutch breeders in this project) are the breeding guidelines suggested by Clare Rusbridge which allow some affected dogs with other valuable qualities to be bred to clear dogs, and which uses the age of 2.5 yrs to fit with the heart protocol (NB CR noted the age was arbitrary but was intended to fit breeders’ use of the heart protocol).

In summary: don’t breed dogs with clinical signs (F dogs); don’t breed dogs with early onset SM (E dogs); breed asymptomatic SM dogs (D)to clear (A/B) dogs; breed at risk (C) dogs with clear (A/B) dogs only.
In the Netherlands, 14 breeders set up the Cavalier Guild for Health and have been screening their dogs since 2000. This is a breeder-led selection of dogs (so no researcher control over which dogs are scanned), and dogs are selected in order to identify the best animals for breeding and with the aim of producing pain-free dogs.

In 2004, 70 dogs were scanned showing a 70% incidence of SM and only 10% were clear A/B dogs. Scanning showed that clear dogs tended to be closely related to other clear dogs while affected dogs were closely related to other affected dogs. By concentrating on screening relatives of clear dogs and screening early -- at 7-18 months to identify good candidate offspring to know which were worth running on -- by 2006 196 different dogs had been screened and about 25% were clear A/B dogs. All sires and dams are screened; puppies are homed with a one year health guarantee.

This breeding programme demonstrates that significant successes can be achieved in only a relatively short period period. Breeders were coping with large numbers of affected dogs -- initially they had very few A dogs and had to do lots of AxD matings. Now, AxA is an option for them. They have had up to four generations “SM clear” (A/B offspring) and no AxA mating has yet produced an affected offspring. SM clear dogs are definitely related to other SM clear dogs and those are the lines the breeders are focusing on.

He hopes to do follow up screenings with dogs to see how they progress.

Identifying genes responsible for the Chiari-like malformation (CM) with or without syringomyelia (SM) will help a better understanding of the underlying pathogenic mechanisms for better diagnosis, prognosis and clinical management of the condition

DNA research should also help unravel the embryonic development of the affected structures that create the malformation

We have constructed a 10,000 dog genealogy of related CKCS spanning 24 generations across three continents (N America, Australia and Europe) and established a DNA collection of 100 samples mainly from CKCS but including 6 other affected breeds (King Charles Spaniels, Yorkshire terrier, Bull terrier, Boston Terrier, Brussels Griffon, Chihuahua)

10 dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosomes. Next, we recently completed the genotyping of 173 CKCS over 249 microsatellite markers distributed over the 28 autosomes and the X chromosome
Because CKCS dogs are so closely related and from a closed gene pool, linkage disequilibrium (LD) analysis is a promising strategy for gene mapping.

Preliminary results of LD analysis identified six statistically significant regions on six associated chromosomes. Possible candidate genes are in the Hox and Pax gene families

Summary of talk:

In humans CM/SM is rare: current estimates are that 1 in 1,290 have the Chiari malformation. SM occurs in 65-80% of humans with Chiari, and 80% experience pain. Genetics are thought to be important but the mode of inheritance is unknown. However, researchers have observed co-segregation with known genetic “bony” (i.e. mesodermal) syndromes e.g. achondroplasia, Klippel-Feil syndrome, primary basilar impression and Goldenhar syndrome. They have also reported familial clustering with vertical and male-to-male transmission consistent with an autosomal dominant mode of inheritance. A human genome scan was recently started and candidate genes are being investigated.

Early observations in the CKCS are:
CM/SM is not simple recessive, but a complex trait -- either polygenic and/or dominant incomplete penetrance or variable expressive is possible.
Clinically affected offspring often have affected (clinically or sub-clinically) parents
Often worse with each generation
At present confirmation only by MRI
All clinically affected dogs share small number of common ancestors (6 out of 8 great-grandparents of all affected dogs can be traced back to two female ancestors)

What is the Chiari malformation? It is thought to involve the somatic mesoderm at the basicranium and craniovertebral junction. There may be para-axial mesoderm insufficiency after the closure of the neural folds. This leads to underdevelopment of the basichondrocranium. The consequence is overcrowding and subsequent herniation of cerebellum into / below the foramen magnum.

Possible candidate genes are:

The Hox family, which controls development of the occipital bone. Ectopic expression of Hox-2.3 results in dysplasia / deficiency of occipital, basisphenoid and atlas bones in transgenic mice (McLain et al. 1992).

The Pax group of genes
Pax-1: which affects somatic segmentation and sclerotomal differentiation in the cervico-occipital transitional zone
Noggin: which affects growth /differentiation somites in the paraxial mesoderm. But: in 33 cases of CM that were analysed, no variants were identified (Speer et al. 2003).

The goals of the genome project are:
Genetic mapping of the CM and SM gene(s) by linkage disequilibrium analysis in the CKCS breed and in other related breeds
Identification of candidate genes for CM and SM using the positional candidate gene approach
Molecular characterization of the gene(s) mutated in CM and associated SM.

Because CKCS dogs are so closely related and from a closed gene pool, linkage disequilibrium (LD) analysis is a promising strategy for gene mapping. Association studies are not possible in this breed because CM is presenting in variable degrees of expression in nearly 100% of the CKCS dogs, so comparison to other breeds is necessary -- especially as closely related breeds are more likely to share ancestral chromosomes and carry the same disease allele.

We have constructed a 10,000 dog genealogy of related CKCS spanning 24 generations across three continents (N America, Australia and Europe) and established a DNA collection of 1000 samples mainly from CKCS but including 6 other affected breeds (King Charles Spaniels, Yorkshire terrier, Bull terrier, Boston Terrier, Brussels Griffon, Chihuahua)

A first goal was to evaluate the informativeness of genetic markers. Ten dogs were selected for genotyping with 122 markers distributed among the 38 autosomes and X chromosomes. In the second genetic analysis, we recently completed the genotyping of 173 CKCS over 249 microsatellite markers distributed over the 28 autosomes and the X chromosome. We looked at multiple affected and unaffected siblings and half siblings and parents. We used Marshfield genotyping services from the NIH (National Institute of Health).

Preliminary results of LD analysis identified six statistically significant regions on six associated chromosomes. Further investigation is ongoing. We are also identifying family clusters of CM/CM in breeds other than CKCS. We have identified CM/SM in nine breeds but we need 10.

Q&A on first two talks:

The earliest case of SM CR has diagnosed was in a 12 week old puppy.
The reason ventricle dilation is recorded on MRI scans is because is may be useful for research as it might indicate an obstruction: ie the start of a syrinx. We don’t really know what to do with that information now but we record it as it may be significant for later research.

CR says she doesn’t know if selecting for a modern head shape has anything to do with the development of SM but says “I think it must have something to do with it -- but the problem is how do you know what factors are relevant. I see all kinds of head shapes in dogs with SM but I can’t find any typical head shape and say, there’s one head shape you should select for.”

CR says in original pedigree analysis all the originally clear dogs did not trace back to the ancestor dogs identified as probable origin of SM in the breed and now a few do but not too many. “Unfortunately a lot of the old, clear dogs are now gone and the lines are completely gone.”
All nine breeds they have found with SM related to CM are short-skulled. Neck and shoulders could be a factor. It hasn’t been seen in cockers. It is rumoured to be in pekes but they have not seen evidence. In King Charles spaniels some are clear of both CM and SM but have hydrocephalus.

Re: summaries of first two talks, London SM seminar

Karlin--thanks for these summaries. I have questions in my mind and then as i'm reading, you answer or address them. The subject of head style and skull shape is so interesting because if only there were some way of de-selecting the anatomical variable in breeding, there would be less of a feeling of being in the dark--if only there were something you could put your finger on and do something about.

So, with the pictures of skull formation and cerebelli posted by Laura Lang in mind, was CR saying that she sees SM not only with the steep drop off skulls but also the long ones that in Laura's pictures show a less compressed cerebellum? In the discussion of those photos, i remain confused about what shape is being associated with the crowded cerebellum, but if i understand right, it's not something you can see just by looking at the shape of the dog's head from the outside?

Was CR's reason for saying she thinks selection for the modern head must have something to do with SM/CM because of the history of cases developing during the same period?

Again, thanks for these summaries, it's a privilege to have them to read.
The Dutch data is so encouraging!

Originally Posted by Karlin

....CR says she doesn’t know if selecting for a modern head shape has anything to do with the development of SM but says “I think it must have something to do with it -- but the problem is how do you know what factors are relevant. I see all kinds of head shapes in dogs with SM but I can’t find any typical head shape and say, there’s one head shape you should select for.”

CR says in original pedigree analysis all the originally clear dogs did not trace back to the ancestor dogs identified as probable origin of SM in the breed and now a few do but not too many. “Unfortunately a lot of the old, clear dogs are now gone and the lines are completely gone.”
All nine breeds they have found with SM related to CM are short-skulled. Neck and shoulders could be a factor. It hasn’t been seen in cockers. It is rumoured to be in pekes but they have not seen evidence. In King Charles spaniels some are clear of both CM and SM but have hydrocephalus.